BIOCHEMICAL CHARACTERIZATION OF OPIOID LIGANDS AND RECEPTORS

阿片类配体和受体的生化特征

• 批准号: 6300719
• 负责人: HENRY I YAMAMURA
• 金额: $ 10.45万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6300719
• 关键词: CHO cells; analgesics; biological signal transduction; chimeric proteins; drug design /synthesis /production; endogenous opioid; enkephalins; ligands; neuropeptides; opioid receptor; peptide analog; peptide chemical synthesis; receptor binding; receptor expression; receptor sensitivity; site directed mutagenesis; stimulant /agonist; synthetic peptide

The treatment of pain associated with surgery, trauma and many diseases states is an essential part of medical practice. Opinoids such as morphine remain the most effective drugs for the treatment of severe pain and are widely used for this purpose despite haveing many serious gastrointestinal, cardiovascular and respiratory side effects. Worst still, these drugs produce a state of physical dependence after repeated use that can lead to addiction. The most effective drugs acting at delta opioid receptors are peptides that cannot enter the central nervous system after conventional routes of administration. New compounds must be made if they are to be useful in the clinic. This proposal seeks to answer the questin, "Can opioid peptide ligands selective for the delta receptor be divided into groups distinguished by their ability to bind this receptor in different ways?" While it is well understood that these drugs must bind opioid receptors to produce effects such as analgesia, marked differences in their chemical structures strongly suggest that they must do so in different ways. If, as this implies, there are different ways for these drugs to bind to the same receptor, then how does this difference affect the way they act? Drugs bind to receptors through contacts with specific receptor amino acids that are in turn encoded by DNA. We propose to modify delta opioid receptors to have amino acid sequences obtained from other opioid receptors (mu an kappa) substituted for existing delta receptor sequences. Such an artificial receptor is called a chimera and it would have drug recognition properties derived from both parent receptors. This kind of large scale modification can be used to narrow down where in the receptor drugs are bound. Individual contacts between receptor amino acids and functional groups of a drug can be determined by selectively changing the DNA sequence encoding a single amino acid using the technique of site-directed mutagenesis. With these two tools we intend to (1) show that chemically defined groups of opioid drugs consistently use particular groups of aiminoacids for delta receptor binding and (2) that the use of these different "recognition sites" is responsible for specific properties of these drugs. This information could revolutionize how new opioid drugs are designed since it defines these drugs by how they interact with delta receptors rather than by their chemical structures.

与手术、创伤和许多疾病相关的疼痛的治疗 疾病状态是医疗实践的重要组成部分。 阿片类药物，如吗啡，仍然是最有效的药物， 治疗严重疼痛，并广泛用于此目的 尽管有许多严重的胃肠道，心血管和 呼吸道副作用 更糟糕的是，这些药物会产生 重复使用后的身体依赖状态，可能导致 成瘾 最有效的药物作用于δ阿片类药物 受体是不能进入中枢神经系统的肽 常规给药途径后的系统。 新 如果要使化合物在临床上有用，就必须制备它们。 这项提案试图回答这样一个问题：“阿片肽 对δ受体具有选择性的配体可分为 通过它们结合这种受体的能力， 方法？“虽然众所周知，这些药物必须结合 阿片受体产生的影响，如镇痛，显着 它们化学结构的差异强烈表明， 他们必须以不同的方式这样做。 如果，正如这意味着， 这些药物与同一受体结合的方式不同， 那么这种差异是如何影响它们的行为方式的呢？ 药物 通过与特定受体氨基接触与受体结合 这些酸又由DNA编码。 我们建议修改 δ阿片受体具有从以下获得的氨基酸序列： 其他阿片受体（μ an kappa）取代现有的 δ受体序列。 这种人工受体被称为 一个嵌合体，它将具有药物识别特性， 两种受体的信号 这种大规模的 修饰可用于缩小受体中 毒品是绑定的。 受体氨基之间的个体接触 药物的酸和官能团可以通过以下方法测定： 选择性地改变编码单个氨基酸的DNA序列， 酸使用定点诱变技术。 与 这两个工具，我们打算（1）表明，化学定义， 阿片类药物的群体一贯使用特定的群体， 用于δ受体结合的氨基酸和（2）使用 这些不同的“识别位点”负责特定的 这些药物的特性。 这些信息可能会彻底改变 如何设计新的阿片类药物，因为它定义了这些药物 通过它们如何与δ受体相互作用，而不是通过它们的 化学结构。